Innovative strategies for tobacco control must be considered. Currently, there are 44 million smokers in the US and 1.2 billion smokers world-wide. Unless there is a dramatic change in the trends, by year 2020, it is anticipated that 7 million smokers will die per year world-wide from tobacco-caused diseases. One approach that has the potential to have significant impact in reducing tobacco-related mortality and morbidity is reducing the nicotine content in cigarettes to levels that are non-addictive. Experimenters of cigarette smoking would have a reduced risk of becoming dependent and dependent smokers would have a greater chance to become smoke-free. Although this measure has been considered as technically feasible, many research gaps need to be addressed before considering nicotine reduction as a policy measure. The goals of this proposal is to address some of the key research gaps including: 1) the best strategy for nicotine reduction (immediate reduction to very low nicotine cigarettes versus gradual reduction in nicotine content of cigarettes), 2) effects of these strategies over time; and 3) identification of factors that may moderate responses to reduced nicotine content (RNC) cigarettes. Smokers will be randomized to three different experimental conditions: 1) very low nicotine content (VLNC) cigarettes with a 0.06 mg nicotine yield (actual dose to be determined by Project 2; N=200); 2) gradual reduction in nicotine content cigarettes (.8 mg, .6 mg, .4 mg, .2 mg and 0.06 mg yield cigarettes, each smoked for a period of 4 weeks, N=200); and 3) usual brand cigarettes as a control group (N=100). Over the 20-week experimental phase, subjects will be assessed for pattern of tobacco use, biomarkers of exposure and effect, subjective responses (e.g., satisfaction, craving withdrawal symptoms), cognitive performance and smoking topography. At the end of the experimental phase, they will be followed for another 4 weeks to assess abstinence from all tobacco products and smoking rate. The results from this study will describe the possible risks and benefits of two approaches for reducing nicotine in cigarettes and help inform future research in this area. This project will complement and use similar measures as Projects 2 and 3.